P898: A PROSPECTIVE PHASE 2 STUDY TO ASSESS MINIMAL RESIDUAL DISEASE AFTER IXAZOMIB, LENALIDOMIDE, DEXAMETHASONE (IRD) TREATMENT FOR NEWLY DIAGNOSED TRANSPLANT ELIGIBLE MULTIPLE MYELOMA PATIENTS
Authors: Raija Silvennoinen, Anu Partanen, Anders Waage, Valdas Pečeliūnas, Fredrik Schjesvold, Pekka Anttila, Katarina Uttervall, Marjaana Säily, Mervi Putkonen, Kristina Carlson, Einar Haukas, Marja Sankelo, Damian Szatkowski, Markus Hansson, Anu Marttila, Per Axelsson, Ronald Svensson, Birgitta Lauri, Maija Mikkola, Conny Karlsson, Johanna Abelsson, Erik Ahlstrand, Anu Sikiö, Monika Klimkowska, Reda Matuzeviciene, Mona Hoyseter Fenstad, Sorella Ilveskero, Hareth Nahi
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Autologous stem cell transplantation (ASCT) proceeded by induction with proteasome inhibitor, immunomodulatory agent, +/- CD38 monoclonal antibody and dexamethasone is the standard of care (SOC) for eligible patients with multiple myeloma. Despite novel drugs, the outcome of high-risk patients is poor. This phase 2 Nordic Myeloma Study Group (NMSG) trial, NCT03376672, investigates the response to ixazomib (I), lenalidomide (R) and dexamethasone (D) (IRD) induction followed by IRD consolidation and risk-based maintenance either with R alone in non-high-risk patients (NHR) or IR in high-risk patients (HR). Here we present the preplanned results for all patients after 2 years on maintenance. Aims: The primary endpoint is the minimal residual disease (MRD) <10-4 (positive or negative) by flowcytometry at any time during treatment compared to the historical Finnish Myeloma Group (FMG) trial (RVD+ASCT+R maintenance). The secondary endpoints include flow-MRD negativity <10-5, overall response rate (ORR), safety, progression-free survival (PFS), results between NHR and HR patients and overall survival (OS). MRD was assessed every 6 months in patients achieving CR. Methods: A written informed consent was obtained from all patients. Altogether 120 patients were included in the study which consisted of 4 IRD cycles as induction, ixazomib 4 mg on days (d) 1, 8, 15, lenalidomide 25 mg on d 1-21, dexamethasone 40 mg weekly in 28-day cycles. Mobilization and single ASCT were performed according to the SOC. Three months post-ASCT patients received 2 IRD consolidation cycles followed by risk stratified maintenance. Patients with del17 (cut of 60%), t(4;14), t(14;16), t(14;20) or +1q were included in HR group and they received ixazomib 4 mg on d 1, 8, 15 and lenalidomide 10 mg on d 1-21/28. If well tolerated, lenalidomide was increased to 15 mg after 3 cycles. At inclusion 52.5% of patients belonged to NHR and 47.5% to HR group. Results: The ORR, at least PR, with induction, was 84%. Forty-three percent (51/120) of patients were MRD <10-4 at any time during protocol treatment versus 45% of historical control. At 2 years on maintenance 40/120 (33%) were ≥CR and 18/40 (45%) also flow-MRD neg <10-5. At 2 years on maintenance 82% of NHR and 74% of HR patients were progression-free (p= 0.395). In the high-risk group, patients with +1q with other HR aberration had the shortest median PFS, 24 (6-48) months. Sustained flow-MRD negativity <10-5 in at least two consecutive samples was detected in 12 patients in the HR group (21%) compared to 12 in the non-HR group (19%), p=0.778. Median PFS for patients with sustained flow-MRD negativity was not reached and was 38 (20-48) months for patients who lost the negativity and 29 (0-47) months for flow-MRD positive patients. OS at 3 year was 92% in NHR and 86% in HR group, p=0.573. Treatment related mortality was 1.7% Pneumonia was the most common grade 3 SAE. Two (1.7%) secondary malignancies were diagnosed: one lung and one pancreas cancer. Summary/Conclusion: The ORR was 84% for IRD induction and 43% had MRD <10-4 at any time during treatment. After 2 years of maintenance 33% of patients were in ≥ CR and 45% of those were also flow-MRD negative <10-5. There was no difference in sustained MRD negativity <10-5 or PFS between HR and NHR patients. The 3-year OS was comparable between NHR and HR groups, 92% vs 86%, respectively. Ixazomib plus lenalidomide maintenance seemed to overcome the worse prognosis for HR in regard to PFS and OS. Keywords: Multiple myeloma, Minimal residual disease (MRD), High risk